This invention relates to certain substituted N-methylene derivatives of the new antibiotic thienamycin. Such compounds and their pharmaceutically acceptable salt, ether, ester, and amide derivatives are useful as antibiotics. This invention also relates to processes for the preparation of such compounds; pharmaceutical compositions comprising such compounds; and methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated.
Thienamycin is disclosed and claimed in U.S. Pat. No. 3,950,357 issued Apr. 13, 1976. This patent is incorporated herein by reference since thienamycin may be employed as a starting material in the preparation of the compounds of the present invention. Thienamycin is known to have the following structure: ##STR2## Starting material I (including all isomers and mixtures of such isomers) is also available by the total synthesis which is described and claimed in co-pending, commonly assigned U.S. patent application Ser. No. 792,071 filed Apr. 28, 1977 now abandoned in favor of U.S. patent application Ser. No. 833,210, filed Sept. 15, 1977, now abandoned in favor of U.S. patent application Ser. No. 17,680, filed Mar. 5, 1979, now U.S. Pat. No. 4,234,596, issued Nov. 18, 1980. This application is incorporated herein by reference since it makes available all isomers, pure and as mixtures, of I which are suitable starting materials for the preparation of the compounds of the present invention.
The compounds of the present invention may be represented by the following structural formulae (II): ##STR3## which structures represent, respectively, one canonical form of a single resonant structure: ##STR4## wherein: R, R.sup.1, R.sup.2, R' and the counter anion A are defined below.
For convenience, the compounds of the present invention may be represented by the following symbolism: ##STR5## or collectively, ##STR6## wherein: (1.) X.dbd.--NR.sup.1 R.sup.2, and Y.dbd.--R'--N.dbd.CRNR.sup.1 R.sup.2 ; and (2.) X.dbd.R, and Y.dbd.--NR.sup.1 R'N.dbd.CRNR.sup.1 R.sup.2 ; "Th" indicates the bicyclic nucleus of thienamycin wherein its hydroxyl, amino and carboxyl functional groups are shown: R is independently selected from the group consisting of hydrogen, --NH.sub.2, --NHR.sup.1, --NR.sup.1 R.sup.2, R.sup.1 and R.sup.2 ; R.sup.1 and R.sup.2 are independently selected from hydrogen, alkoxyl, having 1-6 carbon atoms, R.sup.1 and R.sup.2 may be joined together to form a substituted or unsubstituted mono- or bicyclic heteroaryl or heterocyclyl comprising (together with the nitrogen atom to which they are attached) 4-16 atoms one or more of which may be an additional hetero atom selected from oxygen, sulphur or nitrogen; R, R.sup.1 and R.sup.2 are substituted or unsubstituted: alkyl having from 1 to about 10 carbon atoms; alkenyl having from 2 to about 10 carbon atoms; alkynyl having from 2 to about 10 carbon atoms; cycloalkyl having from 3 to 10 carbon atoms; cycloalkylalkyl and cycloalkylalkenyl having from 4 to 12 carbon atoms; cycloalkenyl, cycloalkenylalkenyl, and cycloalkenylalkyl having 3-10, 4-12 and 4-12 carbon atoms, respectively; aryl having from 6 to 10 carbon atoms, aralkyl, aralkenyl, and aralkynyl having from 7 to 16 carbon atoms; mono- and bicyclic heteroaryl and heteroaralkyl which typically comprise 6 to 16 ring atoms one or more of which is a hetero atom selected from oxygen, sulphur, or nitrogen and wherein the alkyl moiety of the heteroaralkyl radical comprises 1 to about 6 carbon atoms; mono- and bicyclic heterocyclyl and heterocyclylalkyl which typically comprises 4 to 16 ring atoms one or more of which is a hetero atom selected from oxygen, sulphur or nitrogen and wherein the alkyl moiety of the heterocyclylalkyl radical comprises from 1 to about 6 carbon atoms; and wherein the above-mentioned substituent or substituents on R, R.sup.1, R.sup.2 or on the ring formed by the joinder of R.sup.1 and R.sup.2, are selected from the group consisting of: halo, such as chloro, bromo, iodo and fluoro; azido; alkyl having 1-4 carbon atoms; thio; sulpho; phosphono; cyanothio (--SCN); nitro; amine; hydrazino; mono-, di- and trialkyl substituted amino, and hydrazino wherein the alkyl has 1-6 carbon atoms; hydroxyl; alkoxyl having 1-6 carbon atoms; alkylthio having 1-6 carbon atoms; carboxyl; oxo; alkoxylcarbonyl having 1-6 carbon atoms in the alkoxyl moiety, acyloxy comprising 2-10 carbon atoms; carbamoyl and mono- and dialkylcarbamoyl wherein the alkyl groups have 1-4 carbon atoms;
R' is substituted or unsubstituted:
--(CH.sub.2).sub.n (n=1-6), PA1 --CH.sub.2).sub.m --Q--(CH.sub.2).sub.p (n, m=1-3), (Q=S or O), or ##STR7## the substituent on R' is OH, --OR.degree., --SR.degree. or R.degree. (R.degree.=alkyl having 1-4 carbon atoms); the non-critical counter, A, is representatively selected to provide pharmaceutically acceptable salts such as halides (chloro, bromo and the like), sulfate, phosphate, citrate, acetate, benzoate and the like; finally, representative heterocyclic values for R, R.sup.1 and R.sup.2 (defined above) are given in the following table. PA1 R.sup.3.spsp.' is hydrogen, or, inter alia, is representatively selected to provide the pharmaceutically acceptable salt, ester, anhydride (R.sup.3.spsp.' is acyl), and amide moieties known in the bicyclic .beta.-lactam antibiotic art--such moieties are enumerated in greater detail below; and R.sup.3 is: 1.) acyl (generically the group OR.sup.3 is classifiable as an ester); or 2.) R.sup.3 is selected from alkyl, aryl, alkenyl, aralkyl and the like, such that the group OR.sup.3 is generically classifiable as an ether. R.sup.3 may also be hydrogen. The term "acyl" is by definition inclusive of the alkanoyls including derivatives and analogues thereof such as thio analogues wherein the carbonyl oxygen is replaced by sulphur; as well as sulphur and phosphorous acyl analogues such as substituted sulfonyl-, sulfinyl-, and sulfenyl radicals, and substituted P(III and V) radicals such as substituted phosphorous-, phosphoric-, phosphonous- and phosphonic radicals. Such radicals, R.sup.3, of the present invention are enumerated in greater detail below.
______________________________________ Heterocyclyl- Heteroaryl Heteroaralkyl Heterocyclyl alkyl ______________________________________ ##STR8## ##STR9## ##STR10## ##STR11## ##STR12## ##STR13## ##STR14## ##STR15## ##STR16## ##STR17## ##STR18## ##STR19## ##STR20## ##STR21## ##STR22## ##STR23## ##STR24## ##STR25## ##STR26## ##STR27## ##STR28## ##STR29## ##STR30## ##STR31## ##STR32## ##STR33## ##STR34## ##STR35## ______________________________________ [n = 1-6]-
The compounds of the present invention also embrace embodiments of the following structure: ##STR36## wherein: X' is oxygen, sulphur or NR" (R" is hydrogen or R.sup.3.spsp.');
There is a continuing need for new antibiotics. For unfortunately, there is no static effectiveness of a given antibiotic because continued wide scale usage of any such antibiotic selectively gives rise to resistant strains of pathogens. In addition, the known antibiotics suffer from the disadvantage of being effective only against certain types of microorganisms. Accordingly, the search for new antibiotics continues.
Unexpectedly, it has been found that the compounds of the present invention are broad spectrum antibiotics, which are useful in animal and human therapy and in inanimate systems.
Thus, it is an object of the present invention to provide a novel class of antibiotics which possess the basic nuclear structure of thienamycin (I), but which are characterized as the substituted N-methylene derivatives thereof. These antibiotics are active against a broad range of pathogens which representatively include both gram positive bacteria such as S. aureus, Strep. pyogenes, and B. subtilis and gram negative bacteria such as E. coli, Proteus morganii, Klebsiella, Serratia, and Pseudomonas. Further objects of this invention are to provide chemical processes for the preparation of such antibiotics and their non-toxic pharmaceutically acceptable salt, ether, ester and amide derivatives; pharmaceutical compositions comprising such antibiotics; and to provide methods of treatment comprising administering such antibiotics and composition when an antibiotic effect is indicated.